|Principles of Medicinal Chemistry for Inorganics.|
The US Drug Approval Process - Challenges for Metallopharmaceuticals
Cynthia J. Burrows, Ph.D., Professor of Chemistry, Department of Chemistry, University of Utah
David Piwnica-Worms, M.D., Ph.D., Professor, Program in Bioorganic Chemistry, Washington University School of Medicine
Thomas L. Poulos, Ph.D. , Professor, Department of Molecular Biology and Biochemistry, University of California-Irvine
Carolyn J. Anderson, Ph.D., Associate Professor, Department of Radiology, Washington University School of Medicine
Thomas V. O'Halloran, Ph.D., Professor, Department of Chemistry, Northwestern University
Elizabeth C. Theil, Ph.D., Senior Research Scientist, Children's Hospital of Oakland Research Institute
Max Costa, Ph.D., Professor and Chairman, Department of Environmental Medicine, NYU School of Medicine
Chris Orvig, Ph.D., Professor of Chemistry and Pharmaceutical Sciences, Department of Chemistry, University of British Columbia
Craig L. Hill, Ph.D., Goodrich C. White Professor, Department of Chemistry, Emory University
Jill I. Johnson, Special Assistant to the Associate Director, DTP, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Nicholas P. Farrell, Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA, 23284-2006.
Development of small molecules as therapeutic and imaging agents requires not only an understanding of their effects on target biomolecular structure (how the drug works) but also appreciation of the metabolism and pharmacokinetics involved (why the compound is a drug). Successful medicinal inorganic chemistry will intersect synthetic, bioinorganic and medicinal chemistry. Medicinal inorganic chemistry must also situate itself within the current concepts of drug discovery. This contribution will summarize some of these principles using as examples the work in my laboratory on development of novel platinum-containing anticancer agents, which act in ways complementary to the currently used clinical agents.
Supported by NIH and American Cancer Society.
David A. Place, Center for Drug Evaluation Research, Food and Drug Administration, Rockville, Maryland, USA, 20857.
This presentation will provide to developers of metallopharmaceuticals information about special chemistry and regulatory issues that need to be addressed in completing an FDA drug application. Among the issues to be discussed:
The Bicyclam Story: From Metal Complexes to Ligands and Back to Metal Complexes
Michael J. Abrams, Ph.D., AnorMed, Inc., Langley, British Columbia, Canada, V2Y 1N5.
The anti-HIV activity of bicyclams such as AMD-3100 (figure 1) was identified in a program to screen metal complexes and chelators for anti-viral activity. We have recently reported that bis-azamacrocycles such as AMD3100 and certain of their bis-transition metal complexes, inhibit HIV replication by binding to the chemokine receptor CXCR4, the co-receptor used by T-tropic (T-cell tropic) (X4) HIV viruses for membrane fusion and entry of the virus into cells of the immune system (J. Med. Chem. 1995, 38, 366-378; Molecular Pharmacology 1999, 55, 67-73; J. Med. Chem. 1999, 42, 3971-3981; and references therein).
Figure 1: Structure of AMD3100.
In anti-viral activity assays in MT-4 cells, the prototype bicyclam, AMD3100 exhibits an IC50 against HIV-1 (NL4.3, IIIB) and HIV-2 (ROD) replication of 1-10 nM, which is at least 100,000 fold lower than the cytotoxic concentration.
In this lecture, the discovery, SAR and the affect of metal ion coordination on the biological properties of the bicylam class will be discussed.
(IN ORDER OF PRESENTATION)
Stephen J. Lippard, Ph.D., Arthur Amos Noyes Professor & Chair, Department of Chemistry, Massachusetts Institute of Technology
B.A. in chemistry, 1962, Haverford College, Haverford, Pennsylvania; Ph.D. in chemistry, 1965, Massachusetts Institute of Technology; postdoctoral, Massachusetts Institute of Technology. Assistant Professor (1966-1969), Associate Professor (1972-1982), Professor (1972-1982), Department of Chemistry, Columbia University; Professor of Chemistry (1983-1989), Arthur Amos Noyes Professor of Chemistry (1989-present), Head Department of Chemistry (1995-present), Massachusetts Institute of Technology. Sabbaticals: University of Göteborg, Sweden with B. G. Malmström, 1972; MRC Laboratory of Molecular Biology, Cambridge, England with A. Klug, 1979;Anorganisch-Chemisches Institut der Technischen Universität München, Garching, Federal Republic of Germany with W. Herrmann, 1988; Department of Pharmacology, UCSD, San Diego, CA with R. Tsien, 1998.
Honors: Scientific Member, Max-Planck-Gesellschaft; Elected Honorary Member, Italian Chemical, Society; Chair, Gordon Research Conference on Metals in Biology; Honorary D. Sc. Degree, Texas A&M University; William H. Nichols Medal, New York Section of ACS; ACS Award for Distinguished Service in Inorganic Chemistry Sponsored by Mallinckrodt Company; John C. Bailar, Jr. Medal, University of Illinois; Elected to National Institute of Medicine; Elected to National Academy of Sciences; Alexander von Humboldt Senior U.S. Scientist Award; ACS Award in Inorganic Chemistry Sponsored by Monsanto Company; Remson Award, Maryland Section of the American Chemical Society; Elected Fellow, American Academy of Arts and Sciences; Henry J. Albert Award, International Precious Metals Institute; Chairman, Gordon Research Conference on Inorganic Chemistry; Elected Fellow, American Association for the Advancement of Science; Fellow of John E. Fogarty International Center; Fellow of John Simon Guggenheim Foundation; Camille and Henry Dreyfus Teacher-Scholar Award; Fellow of Alfred P. Sloan Foundation; NSF Postdoctoral Fellow; NSF Predoctoral Fellow; Woodrow Wilson Honorary Fellow; Scholastic Achievement Award, Philadelphia Section of ACS; Phi Beta Kappa
PUBLICATIONS (498 total):
B. A. Chemistry, 1975, University of Colorado; Ph. D. Chemistry, 1982, Cornell University; NSF-CNRS Postdoctoral Fellow, 1981-83, Universite Louis Pasteur, Strasbourg; Asst.Prof., Assoc. Prof., Full Prof. 1983-1994, SUNY at Stony Brook, Dept. of Chemistry; Professor of Chemistry, 1995-present, Univeristy of Utah, Department of Chemistry.
Research Interests: Metal-mediated oxidation of DNA, particularly with Ni, Co, Cu and Mn catalysts; metal complexes as probes of DNA and RNA structure; metallopeptides targeted to DNA; sulfite autoxidation by metals and resulting DNA damage; engineering metal catalytic sites into ribozymes.
Thomas J. Meade, Ph.D., Bechman Institute, California Institute of Technology
Thomas J. Meade joined the faculty of the Division of Biology and the Beckman Institute in 1991. He received his BS and MS degrees in chemistry and biochemistry, and a Ph.D. in inorganic chemistry in 1985 from the Ohio State University. He was awarded a NIH post-doctoral fellowship in the department of radiology at Harvard Medical School where he synthesized magnetic resonance imaging agents for organ-specific tumor identification. In 1987 he assumed a postdoctoral appointment in the division of chemistry at the California Institute of Technology where he studied long-range electron transfer reactions in biomolecules.
Dr. Meade's research interests are focused in the areas of inorganic coordination chemistry, bioinorganic chemistry and biological imaging. His work in electron transfer reactions through DNA led to the discovery of a new generation of electronic biosensors of DNA. In 1995 he cofounded Clinical Microsensors that has developed a rapid, chip-based assay for DNA detection.
His work in magnetic resonance imaging has produced a new way to acquire biochemical information in the form of a 3D-MR image. These contrast agents have been shown to monitor in-vivo gene expression and detect intracellular messengers in a noninvasive modality. In 1998 he founded Metaprobe LLC to commercialize these agents for clinical diagnostic radiology.
David Piwnica-Worms received his B.Sc. in Mechanical Engineering from Stanford University and pursued combined M.D.-Ph.D. degrees with dissertation studies under Prof. Melvyn Lieberman in membrane biophysics and physiology at Duke University Medical School. After a residency in diagnostic radiology at the Brigham and Women’s Hospital and a post-doctoral fellowship in magnetic resonance, he joined the faculty of Harvard Medical School. He was promoted to Associate Professor before moving to Washington University Medical School in 1994 were he is now Professor of Radiology and Professor of Molecular Biology & Pharmacology. His research interests include the biochemistry and molecular pharmacology of multidrug resistance mediated by P-glycoprotein and homologous transporters, the utility of novel coordination complexes as radiopharmaceuticals and medicinals, as well as translational research using radiopharmaceuticals for molecular imaging in vivo. As Director of the Molecular Imaging Center and Laboratory of Molecular Radiopharmacology, he leads a multidisciplinary group of scientists focused on research investigations arising at the interface of cancer cell biology, inorganic chemistry and the radiopharmaceutical sciences.
Shubh Sharma, Ph.D., Palatin Technologies, Inc.
Dr. Shubh Sharma is Director of Peptide Research at Palatin Technologies, Inc. (1994-present) He is a peptide chemist with over 18 years of experience in the area of peptide research, drug design and discovery. His recent research interest focuses on development of a novel metallopeptide based drug development platform called “MIDAS,” in which conformationally constrained peptides and combinatorial libraries are developed utilizing a metal ion complexed core structure. His previous research experience include: Research Scientist (1988-1994) in the research group of Prof. Victor J. Hruby of the University of Arizona, Tucson, and Scientific co-worker (1984-1988), in the research group of Prof. Robert Schwyzer, Swiss Federal Institute of Technology, Zurich (ETH-Zurich), Switzerland. He is an inventor on 7 patents and 5 pending patent applications, and is an author on 54 publications.
B.A. in Zoology, Univ. Calif., Santa Barbara,1968; Ph.D. in Biology, Univ. Calif., San Diego, 1973. Research Chemist, UCSD, 1973-1983; Principal Research Scientist & Director Protein Engineering Dept, Genex Corp, 1983 - 1987; Professor of Biochemistry, Univ. of Maryland and Director of Center for Advanced Research in Biotechnology, 1987-1991;. Professor of Molec. Biol. and Biochem.,Univ. Calif., Irvine, 1992-present; Director of Structural Molecular Biology Program in the UCI Cancer Institute; Director UCI Program in Macromolecular Structure; NIH Metallobiochemistry Study Section, 1998-present.
Research interests: Structure and function of hemeproteins; mechanisms of heme enzyme catalyzed oxygen activation reactions and interprotein electron transfer reactions; protein crystallography; mutagenic methods as a probe of protein structure and function.
Selected Recent Publications:
Kenneth M. Merz, Jr., Ph.D., Professor, Department of Chemistry, Pennsylvania State University
B.S. in Chemistry, Washington College, 1981; Ph.D. in Organic Chemistry, The University of Texas at Austin, 1985. Postdoctoral Scholar, Cornell University, 1986-1987; The University of California, San Francisco, 1987-1989. Assistant (1989-1995), Associate (1995-1997), and Professor of Chemistry (1997-present), The Pennsylvania State University. Senior Director, The Center for Informatics and Drug Discovery, Pharmacopeia, Inc. 1998-present.
Fellow, American Association for the Advancement of Science, 1999; Visiting Professor, University of Strasbourg, France, 1998; John Simon Guggenheim Fellowship, 1996-1997; Visiting Professor, University of Strasbourg, France, 1997; Visiting Professor, University of Florence, Italy, 1993; Office of Naval Research-Young Investigator, 1990-1993; National Institutes of Health FIRST Award, 1991-1996; Robert A. Welch Predoctoral Fellow, The University of Texas at Austin, 1982 to 1985; Departmental Competitive Fellowships, The University of Texas at Austin, 1981; Robert A. Welch Summer Research Fellow, The University of Texas at Austin, 1981.
Phi Kappa Phi; American Chemical Society; American Association for the Advancement of Science; New York Academy of Sciences; Biophysical Society; American Physical Society; Protein Society.
Current Research Interests:
The focus of my group is to use computational techniques to further our understanding of biomolecular structure, function and dynamics. Summarized below are the principal research areas that are currently under way in the my research group.
A. Theoretical studies of the structure and function of zinc metalloenzymes. The -lactamases family of enzymes is of greatest current interest. Other zinc metalloenzymes of current and past interest include carboxypeptidase, carbonic anhydrase, liver alcohol dehydrogenase and the zinc finger class of proteins.
B. Exploration of the utility of coupled potential calculations (so-called QM/MM calculations). We are developing and applying new theoretical techniques to use combined quantum and classical mechanical techniques to study reactions in enzymes and in solution.
C. We are developing fully quantum mechanical models that can be applied to the study of the structure and function of biomolecular systems.
Selected Publications 1998-2000 (120 total):
Benjamin J. Burke, Ph.D., Senior Scientist I, Computational Chemistry, Agouron Pharmaceuticals
B.S. Chemistry, 1981, University of Puget Sound, Tacoma, WA.; Ph.D. Medicinal Chemistry, University of Illinois at Chicago, March 1993. Postdoctoral Fellow, Agouron Pharmaceuticals, November 1992-November 1993. Pennwalt Corporation, Inorganic Division, 1981-1986; Agouron Pharmaceuticals, Inc., Research Scientist, 1993-1997;
Agouron Pharmaceuticals, Inc., Senior Scientist I, 1997-present.
Research Projects: HIV-1 Protease, Matrix Metalloprotease, Herpes, HIV-1 Integrase, MetAP2.
Protein-ligand molecular recognition and binding energetics; Development of methods for use in rational design of therapeutic agents; Application of methods to estimate solvent effects; Statistical techniques for solving multivariate problems; Molecular modeling; Molecular similarity; Library design and diversity; ADMET prediction
Representative Publications (from two worlds--QSAR and SBDD):
Shuang Liu, Ph.D., Principal Research Chemist, Medical Imaging Division, Dupont Pharmaceuticals Company
Shuang Liu was born in China. He received his B.S. degree in chemistry at Shandong Normal University in 1982, and then completed his Master's degree in pharmaceutical sciences at Shandong Medical University in 1985. He came to North America in 1987 to pursue his Ph.D. with Professor Robert C. Lucas at Memorial University of Newfoundland, St. John's, Canada, studying the coordination chemistry of macrocyclic thioether ligands with various transition metals. After completion of his Ph.D. in 1990, he spent the next two and half years as a NSERC (Natural Sciences and Enginerring Research Council of Canada) postdoctoral fellow with Professor Chris Orvig at the University of British Columbia, Vancouver, Canada, investigating the coordination chemistry of technetium, aluminum, gallium, indium, and lanthanide metal complexes with various ligand systems. In 1993, he joined DuPont Pharmaceuticals Company as a Senior Research Scientist. He is currently a Principal Research Scientist
in the Medical Imaging Division (North Billerica, MA, U.S.A.). His research
interests include receptor-based target specific radiopharmaceuticals, new
bifunctional chelators, development of new techniques for the radiolabeling of small
biomolecules, and coordination chemistry of metallopharmaceuticals. He is a member of Advisory Board of Bioconjugate Chemistry, author/co-author of 15 US patents or foreign patent applications, and author/co-author of over 60 scientific papers.
B.S. Chemistry, 1985, University of Wisconsin-Superior; Ph.D. Inorganic Chemistry, 1990, Florida State University; Research Associate, Washington University School of Medicine (WUSM), 1990-1992; Assistant Professor, WUSM, 1993-2000; Associate Professor, WUSM, 2000-present.
Research Interests: Development of radiometal-labeled radiopharmaceuticals for diagnostic imaging and targeted radiotherapy of cancer; development of bifunctional chelators for labeling radiometals to biological molecules; metabolism of radiometal-labeled bifunctional-chelate-biological molecule conjugates; mechanisms of cell killing;
Randall B. Lauffer, Ph.D., Chief Scientific Officer, EPIX Medical, Inc.
Dr. Lauffer received his Ph.D. in Chemistry from Cornell University in 1983. At the Massachusetts General Hospital, Boston, MA, he served as a National Institutes of Health Postdoctoral Fellow and as director of the NMR Contrast Media Laboratory. He also held positions of Assistant Professor in Radiology at Harvard Medical School and NIH New Investigator. In 1992, Dr. Lauffer founded EPIX Medical, Inc., a developer of MRI contrast agents, and currently serves as Chief Scientific Officer and a member of the board of directors.
Richard A. Miller, M.D., President and Chief Executive Officer, Pharmacyclics
Dr. Miller is the President, Chief Executive Officer and a Director of Pharmacyclics, a
public biotechnology company, which he co-founded in April 1991. In 1984, Dr.
Miller co-founded IDEC Pharmaceuticals Corporation, a public biotechnology company,
where he served as Vice President and a Director until February 1992. Dr. Miller
also is a Clinical Professor of Medicine (Oncology) at Stanford University Medical
Center. Dr. Miller received his M.D., summa cum laude, from the State University of New York Medical School and is board certified in both Internal Medicine and Medical
Thomas V. O'Halloran (Born May 10,1957) is a Professor in the Department of Chemistry and the Department of Biochemistry, Molecular Biology and Cell Biology of Northwestern University. He is also Director of Research in the Radiation Medicine Institute of Evanston Hospital and serves as Director of the Molecular Oncogenesis Basic Research Group at Northwestern’s Robert E. Lurie Cancer Center.
Prof. O’Halloran’s research interests center on the biology and chemistry of transition series elements. His work focuses on the intracellular inorganic chemistry of zinc, copper, iron and mercury. The results provide insights into human health, cancer and disorders such as Wilson disease and Lou Gehrig’s Disease. In the course of these studies, Prof. O’Halloran and his coworkers have characterized two new classes of soluble metal receptors: the metalloregulatory and metallochaperone protein. This research has been funded by NIH, NSF, ONR, The ALS Association, The Boughton Trust and the Searle Scholars Program of the Chicago Community Trust.
Scientific recognition includes Presidential Young Investigator Award, NSF (1987-92); National Searle Scholars Award, The Chicago Community Trust (1987-90), Alfred P. Sloan Research Fellow (1991-93); The Camille and Henry Dreyfus Foundation Teacher-Scholar Award (1993-95); and American Society of Biochemistry and Molecular Biology Scientific Achievement Award sponsored by Schering-Plough (1996). He is a Fellow of the American Association for the Advancement of Science and a John Simon Guggenheim Fellow.
Professor O’Halloran’s service to the academic and scientific communities currently includes Chairmanship of the Metallobiochemistry Review Panel of the National Institutes of Health, Chairman of the Microbial Stress Response Gordon Conference and Chairman of the General faculty Committee of Northwestern University. Professor O’Halloran will be the Chairman of the Metals in Biology Gordon Conference in 2002. He is currently on the editorial board of Inorganic Biochemistry, Current Opinion in Chemical Biology and the Journal of Biological Inorganic Chemistry. He has served as Chair of the Bioinorganic Subdivision of American Chemical Society and on the board of one of its journals, Inorganic Chemistry.
Prof. O’Halloran’s teaching has been recognized by Mortar Board (Faculty Honor Roll of Outstanding Teachers, 1994); the Associated Student Government (Faculty Honor Roll, 1996); the Interfraternity Council and Panhellenic Association (Award for Excellence in Teaching, 1997); and the Weinberg College of the Arts and Sciences (Leroy Hall Award for Excellence in Teaching, 1998).
Dr. O’Halloran received his bachelor’s and master’s degrees from the University of Missouri, his doctoral degree in Bioinorganic Chemistry from Columbia University, New York; and was a NRSA Postdoctoral Fellow at MIT. He joined the Northwestern faculty in 1986.
Elizabeth C. Theil is currently Senior research Scientist at CHORI, a private research institute owned by Children’s Hospital Oakland and dedicated to basic and clinical research on diseases of children. Theil recently joined CHORI to expand her program on BioIron by creating interfaces for translational research on iron overload in medicine and iron deficiency in nutrition. She chose to leave her chair as University Professor of Biochemistry and Physics at North Carolina State University and join CHORI because the intellectual, scientific and clinical environment. Educated at Cornell and Columbia Universities, and author of over 150 scientific publications, Theil is a leader in the study of BioIron with interests that span Biology and Chemistry, both scientifically and pedagogically. Some of her activities include:
Ferritin, which is the model of gene regulation and protein function that Theil has selected for study, concentrates iron as a solid inside the protein to match cellular requirements that are ~ 1011 times above the solubility of free iron. Oxygen is also trapped during ferritin mineralization, possibly providing an oxygen trap in anerobes. Animals, plants and bacteria all use ferritin. Ferritin pathologies in humans are associated with thalassemia, sickle cell anemia, hemochromatosis, cataracts, infection, and inflammation; deletion of a ferritin gene in mice is lethal early in embryonic development. Plants use ferritin iron for chloroplast maturation and photosynthesis.The premier source of iron in cells for iron protein synthesis and in organisms for normal growth and health is ferritin. Recently ferritin has been shown to correct nutritional iron deficiency and anemia in rats. Iron deficiency affects 30% of the world population negatively influencing productivity, cognitive development and general health. Ferritin is also the first line of defense against excess iron associated with genetic diseases, including hemochromatosis, one of the most prevalent genes in humans of European descent.
Current research studies Theil is directing include molecular studies of the structure and function the IRE family of mRNA regulatory elements and the entry and exit of iron into out of the ferritin protein. In addition, both ferritin mRNA and protein are being developed as targets for chemicals to enhance ferritin biosynthesis (mRNA) or iron chelation (protein) in the management of iron overload. Finally, she is exploring iron homeostasis in transgenic murine models of sickle cell and thalassemia disease and seed ferritin as a bioavailable source of iron in human nutrition.
Kenneth N. Raymond, Ph.D., Professor of Chemistry, Department of Chemistry, University of California
Professor Kenneth N. Raymond was born on January 7, 1942 in Astoria, Oregon. Following his early education in the public schools of Oregon, he attended Reed College where he received a B.A. in 1964. His education was interrupted by a one-year stay in Europe, where he was a test driver and mechanic in Munich. Upon completing his Ph.D. he began his faculty appointment at the University of California at Berkeley on July 1, 1967. There he has remained, becoming Associate Professor in 1974 and Professor in 1978. He has served as Vice Chair of the Berkeley Chemistry Department (1982-1984 and 1999-2000) and Chair (1993-1996). He has been a Visiting Professor or Lecturer at several universities. These include: Stanford University (1973), The Australian National University (1974), Université Louis Pasteur, Strasbourg (1980), University of Rennes (1988), University of Queensland (1989), William Pyle Phillips Distinguished Visitor, Haverford College (1993), 3`eme Cycle Lecturer in Switzerland (1990,1995), Patrick Lecturer, Kansas State University (1996), Endowed Lecturer, University of Oklahoma (1987, 1996), Ernest H. Swift Lecturer, California Institute of Technology (1996) and Sacconi Lecturer, University Florence. He was Chair of the American Chemical Society, Division of Inorganic Chemistry in 1996. He has been an Alfred P. Sloan research fellow (1971-1973), a Miller research professor at the University of California (1977-1978, 1996) and a Guggenheim fellow (1980-1981). He received the Ernest O. Lawrence Award of the Department of Energy in 1984, a Humboldt Research Award for Senior U.S. Scientists in 1991, the American Chemical Society Alfred Bader Award in Bioinorganic or Bioorganic Chemistry in 1994. He was elected to the National Academy of Sciences in 1997. He was also selected Basolo Medalist at Northwestern University in 1997 and received the Max-Planck-Institut für Strahlenchemie “Frontiers in Biological Chemistry” award.
Professor Raymond is a member of the editorial board of several journals in the fields of inorganic and bioinorganic chemistry. In addition to his academic appointment on the University of California campus, he is a Faculty Senior Scientist of the Chemical Sciences Division, Lawrence Berkeley National Laboratory. He is the author of ten patents and over 310 research publications.
Early in his career at Berkeley, Professor Raymond determined the structure of uranocene (then newly prepared by Streitwieser and coworkers) and went on to characterize structurally a large number of other organo-actinide and organo-lanthanide compounds. He completed his contribution to this field with the development of an ionic radii model that successfully predicted these molecular structures and which continues to be used in this growing area of organometallic chemistry. Professor Raymond is a pioneer of the field of bioinorganic chemistry with his research in biological iron transport, particularly siderophore mediated iron transport in microorganisms. The characteristics of coordination chemistry of the siderophores, and the role that molecular recognition plays in microbial iron transport, have been major contributions of Raymond's research. He and his research group were the first to use kinetically inert metal-substituted complexes of siderophores to elucidate the cellular transport mechanisms of iron in microorganisms. Using such complexing agents as prototypes, Professor Raymond and coworkers have designed and synthesized sequestering agents specific for individual metal ions. In the case of plutonium the similar chemical and biochemical properties of Pu(IV) and Fe(III) (which is a basis for the biohazard of plutonium) has been exploited by Raymond and coworkers to prepare ligands that are highly specific for Pu(IV). Several of these compounds have been shown to be highly effective Pu decontamination agents. A focus of Raymond's current research is using coordination chemistry as the driving force in the rational design and preparation of symmetry-driven supramolecular assemblies. The host-guest chemistry of these supermolecules presents new opportunities for chemical reactions.
Relevant Publications (1996-present):
Richard A. Anderson, Ph.D., Lead Scientist, USDA, Beltsville Human Nutrition Research, United States Department of Agriculture
Lead Scientist at the Beltsville Human Nutrition Research Center studying the nutritional role of chromium and other trace elements in human health and disease. Research includes determining the effects of various forms of stress including high sugar diets, exercise, temperature and physical trauma on trace element metabolism. Studies are conducted on humans, large and small animals and cell culture studies.
My research interests center along the molecular mechanisms of nickel and chromium carcinogenesis. These two metals differ strikingly in their carcinogenic action. The most carcinogenic nickel compounds are the water-insoluble compounds that become phagocytized by cells and deliver high concentrations of nickel inside the cell. Nickel is able to induce chromosomal aberrations and also causes DNA hypermethylation which inactivates the transcription of tumor suppressor genes. In yeast, nickel is capable of silencing genes placed near the telomere binding element. Chromium has a very different mechanism of action in that it forms DNA adducts and crosslinks amino acids, such as cysteine, glutathione, and protein to DNA. Chromate appears to be doing this by binding to the phosphate backbone of DNA and preferentially binds to guanine as well. The Cr-DNA adducts are quite stable, however, they can be removed by EDTA and we have used UvrABC in combination with ligation-mediated PCR to map Cr-DNA adducts in collaboration with Dr. E. Tang in our department.
Chris Orvig was born and raised in Montréal. He received his B.Sc. in chemistry from McGill University in 1976 and, after a year as an itinerant skier, he subsequently pursued graduate studies (as a Natural Sciences and Engineering Research Council - NSERC – of Canada scholar) in technetium chemistry at M.I.T. with Prof. Alan Davison, receiving the Ph.D. in 1981. He was then an NSERC postdoctoral fellow with Prof. Kenneth N. Raymond at the University of California, Berkeley in 1981-83. After one year with the late Prof. Colin J. L. Lock at McMaster University, he joined the University of British Columbia in 1984, where he is now Professor of Chemistry and Pharmaceutical Sciences, and Director of the Medicinal Inorganic Chemistry Group. His scientific interests are firmly planted in the areas of medicinal inorganic chemistry and coordination chemistry – he has been involved over the years with radiopharmaceutical chemistry, metal ion decorporation, metal ion neurotoxicology, and chemotherapeutic metal complexes.
Orvig is the inorganic chemistry editor of Can. J. Chem. and sits on numerous editorial boards. He has received various research and teaching awards, has published more than 100 research papers, is a co-inventor on many issued patents (including eight from the USA), and is a certified ski instructor. He is, until late summer 2000, on sabbatical leave as a Humboldt Research Award winner in Münster, Germany with Prof. Dr. F. E. Hahn, and travelling the world delivering lectures.
Dennis P. Riley, Ph.D., Vice-President for Research & Development, Research and Development, MetaPhore Pharmaceuticals, Inc.
Dennis P. Riley joined MetaPhore Pharmaceuticals, Inc. as Vice-President of R&D in April, 1999. MetaPhore Pharmaceuticals is focused on the development of both chelation therapies and the use of metal complexes as pharmaceuticals; especially small molecule functional enzyme mimics. He joined MetaPhore following his career at Monsanto as a Senior Science Fellow and manager of Metal-Mediated Chemistry in Monsanto's Corporate Research Division. He completed his undergraduate education with majors in chemistry and mathematics (cum laude) at Heidelberg College and earned his Ph.D. at Ohio State University in inorganic coordination chemistry in 1975 with Professor Daryle Busch. Following post-doctoral training in homogeneous catalysis at the University of Chicago in the laboratories of Professor Jack Halpern and several years at Procter & Gamble (becoming Section Head for process chemistry and bioinorganic chemistry), he joined Monsanto's Corporate Research center in St. Louis as Senior Research Group leader in Homogeneous Catalysis. Dr. Riley is an Adjunct Professor of chemistry at Washington University, has been elected a Fellow of the American Association for the Advancement of Science, elected Chairperson and organizer of the 1998 Gordon Research Conference on Inorganic Chemistry, and he was the recipient of the ACS St. Louis Section's 'Chemist of the Year' Award for 1999. His primary research interests include bioinorganic chemistry (Synzymes --small molecule functional mimics of enzymes), activation of small molecules (i.e., O2 and CO2), catalytic oxidations, and asymmetric catalytic conversions. He has been granted over thirty US patents and over 200 foreign patents; as well as published over 80 papers and authored several review articles and book chapters.
Craig L. Hill received his Ph.D. from M.I.T. in 1975 under the direction of George M. Whitesides. After a NSF postdoctoral fellowship at Stanford with Richard H. Holm, and an Assistant Professorship at the University of California at Berkeley, he joined the faculty at Emory University where he is currently Goodrich C. White Professor. His research interests include the design of catalysts for challenging or environmentally benign processes, and the design of catalytic systems (both molecules and materials) that buffer themselves, repair damage and catalyze more than one reaction ("intelligent" catalysts) (funded by NSF, ARO, ONR, DOE and industry). His group also investigates the fundamental chemical, physical and biological properties of large multicomponent and multifunctional molecules such as polyoxometalates (funded by NIH, ARO, and industry). One subset of this is the mechanisms of action of polyoxometalate antiviral agents. His recent awards include a Humboldt Senior Scientist Award (1995), the USDA National Award for Group Excellence in Research (shared with colleagues at the Forest Products Laboratory) (1996) for the development of a new pollution-free catalytic aerobic technology to convert trees (wood pulp) to paper, and the Albert E. Levy Award from Sigma Xi (1996). Currently or recently he has served several journals (editing or editorial boards) and national panels (NAS, NSF and NIH). He enjoys time with his domestic and research families and yearly mountaineering and other adventures in the Americas and Eurasia.
Jill Johnson has worked for the Developmental Therapeutics Program for more than 20 years. For the majority of this time she has assisted the Program in the acquisition of compounds for screening as potential anti-cancer agents, and is therefore very familiar with the history of the screening program. She has managed the plating of the DTP repository of >140,000 non-proprietary compounds, and managing the distribution of this resource to approved researchers in the extramural community. Jill was recently promoted to the position of Special Assistant to the Associate Director of DTP, which involves creating liaisons with the anti-cancer research community and setting program short and long-term goals.